Changes in urine flow rate, glomerular filtration rate and sodium, potassium and chloride excretion rates were monitored after the i.v. and renal arterial administration of N-ethylmaleimide (NEM) to dogs. Intravenous administration of NEM (72.9 and 117 mumol/kg) failed to induce an increase in any of the parameters mentioned. Renal arterial injection of 36.5 mumol/kg of NEM appeared to be nephrotoxic, whereas doses of 8.00 and 0.80 mumol/kg were associated with rapid and sustained increases in urine flow rate and the excretion rates of sodium, potassium and chloride. No changes in renal function were noted when the renal arterial dose of NEM was reduced to 0.08 mumol/kg. Three potential biotransformation products of NEM [i.e., N-ethylmaleamic acid; the cysteine adduct of NEM (NEM-cysteine); and the glutathione adduct of NEM (NEM-glutathione)] failed to induce an increase in any of the functional parameters studied regardless of the route of administration. We conclude that NEM is diuretic in the dog, but only after injection directly into the renal artery. The observed diuresis appears to be: 1) induced by NEM itself rather than by one of its potential biotransformation products, 2) due to its relatively irreversible alkylating property and 3) either a manifestation of the renal toxicity elicited by this agent or an independent effect that simply occurs at doses similar to those that induce renal injury.